Project Summary/Abstract - Project 1: Adenocarcinoma of the pancreas is the 4th leading cause of cancer death in the U.S. Metastasis is a major cause of cancer mortality, accounting for as many as 90% of cancer-related deaths. Although a goal of cytotoxic therapies is to minimize metastatic tumor growth, therapies specifically designed to inhibit the mechanisms of invasion that drive metastasis are not currently utilized as a part of pancreatic cancer treatment. We believe that targeting invasion and metastasis of pancreatic tumors should be considered as an important goal when treating pancreatic cancer, even in the absence of detectable metastatic disease. This proposed research program will investigate the use of pharmacologic ascorbate (P-AscH-, high-dose, IV delivery of vitamin C) in the treatment of pancreatic cancer. Intravenous ascorbate, but not oral ascorbate, produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We have firmly established that P-AscH- is a pro-drug for delivery of hydrogen peroxide (H2O2) in tumor cells. Recent clinical studies have demonstrated that P-AscH- is safe and well tolerated. In addition, patients with stage IV pancreatic cancer did not develop metastatic disease, had reductions in metastases during treatment, and increased median survival from 6 months to 16 months. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical events in pancreatic cancer metastases. HIF-1? mediates hypoxia responses and is overexpressed in pancreatic cancer. Stabilization and activation of HIF-1? triggers its target genes related to metastasis, which correlate with many difference cellular processes, such as proliferation, angiogenesis and EMT. The current proposal will test the hypothesis that production of H2O2 mediates P-AscH--induced inhibition of metastatic disease in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims: 1) Determine if P-AscH- reduces metastatic disease by inhibiting the EMT process and tumor cell invasion via a H2O2-mediated mechanism; 2) Determine if decreased expression of H2O2-metabolizing enzymes (i.e., catalase) in metastatic PDAC cells mediates the increased sensitivity to P-AscH?. 3) In a phase II trial, determine efficacy of P-AscH? combined with gemcitabine/nab-Paclitaxel as defined by an increase in progression free survival and/or overall survival. Our proposal combines complimentary approaches to demonstrate that P-AscH- can be used successfully as an adjuvant to improve responses in the treatment of pancreatic cancer. Furthermore, we will investigate the mechanism by which P-AscH- inhibits metastatic disease. If we can rigorously demonstrate that P-AscH- induces preferential oxidative stress and subsequent inhibition of metastatic disease in pancreatic cancer, then the results of this proposed research program will provide a foundation for the rational design of a combined modality cancer therapy.